Allergology International xxx (2016) 1e27 Contents lists available at ScienceDirect Allergology International journal homepage: http://www.elsevier.com/locate/alit Invited review article Japanese guidelines for adult asthma 2017* Masakazu Ichinose a, *, Hisatoshi Sugiura a, Hiroyuki Nagase b, Masao Yamaguchi b, Hiromasa Inoue c, Hironori Sagara d, Jun Tamaoki e, Yuji Tohda f, Mitsuru Munakata g, Kohei Yamauchi h, Ken Ohta i, The Japanese Society of Allergology a Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan d Division of Allergology and Respiratory Medicine, Department of Medicine, Showa University, School of Medicine, Tokyo, Japan e First Department of Medicine, Tokyo Women's Medical University, Tokyo, Japan f Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osaka, Japan g Department of Pulmonary Medicine, School of Medicine, Fukushima Medical University, Fukushima, Japan h Division of Pulmonary Medicine, Allergy and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan i National Hospital Organization, Tokyo National Hospital, Tokyo, Japan b c a r t i c l e i n f o a b s t r a c t Article history: Received 12 September 2016 Available online xxx Adult bronchial asthma is characterized by chronic airway inflammation, and presents clinically with variable airway narrowing (wheezes and dyspnea) and cough Long-standing asthma induces airway remodeling, leading to intractable asthma The number of patients with asthma has increased; however, the number of patients who die of asthma has decreased (1.2 per 100,000 patients in 2015) The goal of asthma treatment is to enable patients with asthma to attain normal pulmonary function and lead a normal life, without any symptoms A good relationship between physicians and patients is indispensable for appropriate treatment Long-term management by therapeutic agents and elimination of the causes and risk factors of asthma are fundamental to its treatment Four steps in pharmacotherapy differentiate between mild and intensive treatments; each step includes an appropriate daily dose of an inhaled corticosteroid, varying from low to high levels Long-acting b2-agonists, leukotriene receptor antagonists, sustained-release theophylline, and long-acting muscarinic antagonist are recommended as add-on drugs, while anti-immunoglobulin E antibody and oral steroids are considered for the most severe and persistent asthma related to allergic reactions Bronchial thermoplasty has recently been developed for severe, persistent asthma, but its long-term efficacy is not known Inhaled b2-agonists, aminophylline, corticosteroids, adrenaline, oxygen therapy, and other approaches are used as needed during acute exacerbations, by choosing treatment steps for asthma in accordance with the severity of exacerbations Allergic rhinitis, eosinophilic chronic rhinosinusitis, eosinophilic otitis, chronic obstructive pulmonary disease, aspirin-induced asthma, and pregnancy are also important issues that need to be considered in asthma therapy Copyright © 2016, Japanese Society of Allergology Production and hosting by Elsevier B.V This is an open access Keywords: Definition of asthma Diagnosis of asthma Epidemiology of asthma Long-term management of asthma Management of asthma exacerbation article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) * This article is an updated version of “Japanese guideline for adult asthma 2014” published in Allergol Int 2014:63; 293e333 * Corresponding author Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan E-mail address: ichinose@rm.med.tohoku.ac.jp (M Ichinose) Peer review under responsibility of Japanese Society of Allergology Aim of the management, definition, type, diagnosis, and severity of asthma 1.1 Definition and pathophysiology of asthma Adult bronchial asthma (hereinafter, asthma) is characterized by chronic airway inflammation, clinically presenting variable airway narrowing (wheezes and dyspnea) and cough Airway narrowing is reversible, and derives from airway inflammation and hyperresponsiveness Pathological analyses in asthma demonstrate chronic airway inflammation accompanied by the infiltration of proinflammatory cells such as eosinophils, lymphocytes, mast cells, and others, and by the detachment of the airway epithelial cells.1,2 http://dx.doi.org/10.1016/j.alit.2016.12.005 1323-8930/Copyright © 2016, Japanese Society of Allergology Production and hosting by Elsevier B.V This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/) Please cite this article in press as: Ichinose M, et al., Japanese guidelines for adult asthma 2017, Allergology International (2016), http:// dx.doi.org/10.1016/j.alit.2016.12.005 M Ichinose et al / Allergology International xxx (2016) 1e27 While many patients are atopic, i.e., positive for immunoglobulin E (IgE) antibodies against environmental allergens, airway inflammation and lymphocyte activation are present even in patients without allergen-specific IgE antibodies The etiology of asthma is multifactorial, and its clinical picture varies greatly among patients Some asthmatic patients demonstrate airway inflammation, predominantly involving neutrophils Long-standing inflammation will damage airways, and induces airway remodeling, entailing subepithelial fibrosis under the basement membrane, smooth muscle hypertrophy, and submucosal gland hyperplasia This results in intractable asthma, presenting irreversible airflow limitation and persistent airway hyperresponsiveness.3 1.2 Aim of the management and treatment of asthma The aim of asthma management and treatment is to improve airway hyperresponsiveness and airflow limitation by eliminating inducers of airway inflammation, by adopting pharmacotherapy to alleviate inflammation, and by dilating the constricted airway (Table 1) In this way, respiratory function can hopefully be normalized to improve the patients' quality of life (QOL) and enable them to lead a normal and healthy life without exacerbations or asthma-related death 1.3 Phenotype/endotype Asthma patients are characterized by widely variable clinical pictures; asthma is thus often recognized as a syndrome, and is classified into several phenotypes Recent progress in genetics and molecular biology has led to the etiological and/or pathogenetic classification of the condition into endotypes 1.4 Diagnosis of adult asthma Generally, clinical diagnosis of asthma is based on the following factors (Table 2): (1) repetitive symptoms, such as paroxysmal dyspnea, wheezing, chest tightness, and cough; (2) reversible airflow limitation; (3) airway hyperresponsiveness; and (6) exclusion of other cardiopulmonary diseases (Table 3) (4) An atopic state and (5) airway inflammation, which is usually indicative of eosinophilia, support a diagnosis of asthma Diagnosing mild asthma in the absence of either wheezes or dyspnea can be difficult 1.4.1 Recurrence of paroxysmal dyspnea, wheezing, chest tightness, and cough Asthma symptoms often occur at night and in the early morning Repeated exacerbations occur amid symptom-free intervals and develop even at rest Patients with asthma may experience dyspnea (choking) during exercise and while performing laborious work 1.4.2 Reversible airflow limitation Wheezing and dyspnea during attacks are induced by reversible airway narrowing, which occurs diffusely throughout the airways and ranges from mild to severe In its mild form, it can be detected only by respiratory function tests, while in its severe form, it could induce near-fatal exacerbations The peak expiratory flow (PEF) and Table Aims of asthma treatment To lead a normal and healthy life To prevent the development of irreversible airway remodeling and maintain normal respiratory function: Peak expiratory flow (PEF), !80% of the predicted value; PEF variation, MF-DPI > CIC-HFA ¼ BDP-HFA > mm These agents are extensively dispersed in the airway, generally, with smaller particles reaching further into the peripheral airway.21 In addition, the effects of fluticasone furoate ester (FF)/LABA (vilanterol), a new ICS (FF)/LABA combination, are sustained for 24 h BUD inhalation suspension, inhaled using a nebulizer, has been introduced, and a jet nebulizer, not an ultrasonic nebulizer, is recommended for BUD inhalation suspension In general, BUD inhalation Please cite this article in press as: Ichinose M, et al., Japanese guidelines for adult asthma 2017, Allergology International (2016), http:// dx.doi.org/10.1016/j.alit.2016.12.005 M Ichinose et al / Allergology International xxx (2016) 1e27 Table 12 Controllers (agents for long-term management) Corticosteroids 1) Inhaled corticosteroids i) Beclomethasone dipropionate ii) Fluticasone propionate iii) Budesonide iv) Ciclesonide v) Mometasone furoate 2) Oral corticosteroids Long-acting b2 agonists 1) Inhalants Salmeterol xinafoate 2) Patch Tulobuterol 3) Oral medicines Procaterol hydrochloride Clenbuterol hydrochloride Formoterol fumarate Tulobuterol hydrochloride Mabuterol hydrochloride Combination inhaler of corticosteroid/long-acting b2 agonist 1) Combination inhaler of fluticasone propionate/salmeterol xinafoate 2) Combination inhaler of budesonide/formoterol fumarate 3) Combination inhaler of fluticasone propionate/formoterol fumarate 4) Combination inhaler of fluticazone furate/vilanterol trifenatate Leukotriene receptor antagonists 1) Pranlukast hydrate 2) Montelukast sodium Theophylline sustained-release preparation Long-acting muscarinic receptor antagonist Tiotropium bromide hydrate Anti-IgE Antibody Omalizumab Anti-allergics other than leukotriene receptor antagonists 1) Mediator antireleasers Sodium cromoglicate, tranilast, amlexanox, repirinast, ibudilast, tazanolast, and pemirolast potassium 2) Histamine H1 receptor antagonists Ketotifen fumarate, azelastine hydrochloride, oxatomide, mequitazine, and epinastine hydrochloride 3) Thromboxane inhibitors i) Thromboxane-A2 synthesis inhibitor Ozagrel hydrochloride ii) Thromboxane-A2 receptor antagonist Seratrodast 4) Th2 cytokine inhibitor Suplatast tosilate Other agents and therapies (Chinese medicines, specilic immunotherapy, and non-specific immunotherapy) exacerbations can be alleviated by increasing the ICS dose.19 Smoking not only reduces the effects of ICSs, but also impairs the respiratory function in asthmatic patients.23 Localized adverse effects, such as oropharyngeal candidiasis and hoarseness can sometimes become problematic, although ICSs have a few systemic adverse effects compared with other steroid formulations After inhalation, gargling or drinking water is essential to alleviate oropharyngeal symptoms and to reduce systemic absorption While the inhibitory effects on adrenal glands in conventional doses are generally acceptable, a careful follow-up of adrenal gland function is necessary when high doses are used BUD-DPI, which can be administered even during early pregnancy, has not been reported to cause congenital malformation or to have any effects on the course of pregnancy.24 The US Food and Drug Administration (FDA) has certified the safety of BUD-DPI in pregnant women as Category B There is no evidence of the increased risk of respiratory tract infection, including tuberculosis, caused by ICSs in patients with asthma, and ICSs are not contraindicated in patients with active tuberculosis suspension at a dose of 0.5 mg twice daily or mg once daily (maximum mg/day) is used for adults ICSs are considered to be the first choice agents for asthma treatment The dosage of ICSs is classified into high dose (the highest dose covered by health insurance), medium dose (half of the high dose), and low dose (half of the medium dose) (Table 14) In adult asthmatic patients, ICSs are effective even at relatively low doses (e.g., 200 mg/day FP) On the other hand, if the dosage exceeds the high dose, further effects proportional to the dose cannot be achieved, and the risk of adverse effects increases.22 Thus, in controlling asthma, adding or more controller other than ICSs, rather than simply increasing the dose of an ICS, should be recommended.19 However, severe acute Table 13 Device for inhaled corticosteroids Pressurized metered dose inhaler (pMDI) Dry powder inhaler (DPI) BDP (beclomethasone dipropionate) BDP-HFA (Qvar®) None FP (fluticasone propionate) FP-HFA (Flutide® Air) FP-DPI (Flutide® Diskus, Flutide® Diskhaler) Combination inhaler with SM (salmeterol xinafoate) FP/SM HFA (Adoair® aerosol) FP/SM DPI (Adoair® Diskus) Combination inhaler with FM (formoterol fumarate hydrate) FP/FM (Flutiform®) None None BUD-DPI (Pulmicort® Turbuhaler) BUD (budesonide) Combination inhaler with FM (formoterol fumarate hydrate) None BUD/FM (Symbicort® Turbuhaler) CIC (ciclesonide) CIC-HFA (Alvesco®) None MF (mometasone furoate) None MF-DPI (Asmanex® Twisthaler) None FF (fluticazone furate) Combination inhaler with VI (vilanterol trifenatate) FF/VI-DPI (Relvar® Ellipta) Table 14 Recommended doses of inhaled corticosteroids by treatment steps Agent Treatment steps 1e2/low dose Treatment steps 2e3/medium dose Treatment steps 4/high dose BDP-HFA 100e200 mg/day 400 mg/day 800 mg/day FP-HFA 100e200 mg/day 400 mg/day 800 mg/day CIC-HFA 100e200 mg/day 400 mg/day 800 mg/day FP-DPI 100e200 mg/day 400 mg/day 800 mg/day MF-DPI 100e200 mg/day 400 mg/day 800 mg/day BUD-DPI 200e400 mg/day 800 mg/day 1600 mg/day BIS 0.5 mg/day 1.0 mg/day 2.0 mg/day BDP-HFA, beclometasone dipropionate hydrofluoroalkane; FP-HFA, fluticasone hydrofluoroalkane; CIC-HFA, ciclesonide hydrofluoroalkane; FP-DPI, fluticasone propionate dry powder inhaler; MF-DPI, mometasone furoate dry powder inhaler; BUD-DPI, budesonide dry powder inhaler; BIS, budesonide inhalation suspension Please cite this article in press as: Ichinose M, et al., Japanese guidelines for adult asthma 2017, Allergology International (2016), http:// dx.doi.org/10.1016/j.alit.2016.12.005 M Ichinose et al / Allergology International xxx (2016) 1e27 b) Long-acting b2 agonists (LABAs): b2-agonists bind to b2 receptors in airway smooth muscle, relaxing the airway smooth muscle These are potent bronchodilators that enhance airway mucus removal by activating epithelial cilia, and are administered via inhalation, patches, and the oral route b2-Agonists should be used concomitantly with ICSs as controllers When a LABA is combined with an ICS, the steroid increases the number of b2-receptors, and the b2-agonist amplifies the nuclear translocation of steroid receptors and further enhances the effects of the steroid Furthermore, ICS/LABA allows reduction of the ICS dose,25 and improves the control of asthma Combination of an ICS and LABA is more effective than an ICS with sustained-release theophylline.26 Salmeterol xinafoate (SM) is an inhaled LABA that cannot be used as monotherapy for the treatment of asthma27; however, it has strong synergistic effects when combined with an ICS.28 Conventional oral LABAs include procaterol hydrochloride, clenbuterol hydrochloride, and mabuterol hydrochloride A tulobuterol patch, which was developed in Japan, is a long-acting agent with a bronchodilatory action that lasts for 24 h It is useful for patients in whom inhalation and oral administration are difficult Its clinical usefulness when combined with an ICS has been reported.29 Although LABAs have a high safety profile in any formulation, they sometimes have adverse effects, including tremor, palpitations, and tachycardia, which occur most frequently for oral agents, followed by patches, and inhaled agents When adverse effects are observed, the dose should be reduced or administration should be discontinued Serious adverse effects include a decreased serum potassium level LABAs should be used more carefully in asthmatic patients with ischemic heart disease, hyperthyroidism, and diabetes mellitus The adverse effects of the tulobuterol patch are skin itching or rash (or both) around the patch area c) Combination agents comprised of ICS and inhaled LABA (ICS/LABA) (Table 15): combined inhalation of ICS and LABA are more effective than their separate inhalation.30 In Japan, FP/salmeterol (SM), BUD/formoterol (FM), Table 15 Suggested daily doses of a combination inhaler containing corticosteroids and longacting b2 agonists Low dose Medium dose High dose FP/SM (DPI) 100 mg/dose, dose b.i.d 200 mg/100 mg 250 mg/dose, dose b.i.d 500 mg/100 mg 500 mg/dose, dose b.i.d 1000 mg/100 mg BUD/FMy (DPI) One dose b.i.d 320 mg/9 mg Two doses b.i.d 640 mg/18 mg Four doses b.i.d 1280 mg/36 mg FP/SM (pMDI) 50 mg/dose, doses b.i.d 200 mg/100 mg 125 mg/dose, doses b.i.d 500 mg/100 mg 250 mg/dose, doses b.i.d 1000 mg/100 mg FP/FM (pMDI) 50 mg/dose, doses b.i.d 200 mg/20 mg 125 mg/dose, doses b.i.d 500 mg/20 mg 125 mg/dose, doses b.i.d 1000 mg/40 mg FF/VI (DPI) 100 mg/dose, dose s.i.d 100 mg/25 mg 100 mg/dose, dose s.i.d 100 mg/25 mg or 200 mg/dose, dose s.i.d 200 mg/25 mg 200 mg/dose, dose s.i.d 200 mg/25 mg FP, fluticasone propionate; SM, salmeterol xinafoate; BUD, budesonide; FM, formoterol fumarate; FF, fluticazone furate; VI, vilanterol trifenatate y Indication in a delivered dose fluticasone furoate ester (FF)/FM, and FF/vilanterol (VI) are used as combination ICS/LABA agents The formulations of FP/SM, BUD/FM, FF/VI are available as DPI and FF/ FM as pMDI The advantages of the ICS/LABA combination are (i) the number of inhalations can be reduced; (ii) excellent adherence can be achieved; and (iii) the use of LABAs alone can be avoided Furthermore, the rescue use of the FM formulation instead of a short-acting b2-agonist (SABA) can improve asthma symptoms and reduce the rate of asthma exacerbations (single maintenance and reliever therapy: SMART).31 SMART treatment has been approved in Japan since 2012 On the other hand, SMART carries the risk of promoting poor adherence to regular therapy as well as excessive use, as the patients can determine their own treatment Therefore, it is important to select patients for SMART carefully and educate them FF/VI is expected to achieve higher adherence, because it requires once-daily use According to the 2010 FDA recommendations, asthma treatment should be based on an assessment of the level of control when using these combination agents.32 If the simultaneous use of LABA can be discontinued when asthma is well controlled, a switch to ICS monotherapy can be made However, it remains controversial whether combination agents should be continued after good control of asthma is achieved, because they can reduce the rate of severe exacerbations as compared to ICSs monotherapy.33,34 Viral infection is a major cause of asthma exacerbations Combination ICS/ LABA agents are reported to be superior to ICS monotherapy for reducing exacerbations due to viral infection.35,36 d) Leukotriene receptor antagonists (LTRAs): leukotrienes (LT) C4, D4, and E4, are termed cysteinyl LTs (CysLTs), and bind to the CysLT1, CysLT2, and CysLT3 receptors, respectively A currently available LTRA is a CysLT1 receptor antagonist, which includes pranlukast hydrate and montelukast in Japan LTRAs have a bronchodilator action and inhibit airway inflammation, resulting in significant improvement of asthma symptoms and respiratory function; allow as-needed inhalation of a b2-agonist, reduce airway inflammation, airway hyperresponsiveness, the dosage of ICSs, and asthma exacerbations; and improve patients' QOL37e39 LTRAs are used concomitantly with an ICS in patients with asthma that cannot be completely controlled even with a medium dose of an ICS, because the additional administration of LTRAs is as effective as a double-dose of an ICS.40 Compared with LABAs, LTRAs used in combination with an ICS are less effective in improving asthma symptoms and respiratory function and in preventing exacerbation; the equivalent effects in oral LTRAs compared to LABAs may be due to excellent adherence.41 LTRAs are useful for long-term management of patients with asthma complicated by allergic rhinitis, exercise-induced asthma (EIA), and aspirin-exacerbated respiratory disease (AERD) Generally, LTRA monotherapy is less effective than that with low-dose ICSs in mild asthmatic patients.42,43 The oral administration of an LTRA improves pulmonary function in some patients (at several hours at the earliest, on the following day at the latest); however, their antiinflammatory effects develop later Thus, efficacy is generally judged only after 2e4 weeks of administration Nevertheless, the effects of LTRAs have not been established in acute asthma exacerbations.44 While more reports have been published on EGPA in patients who have Please cite this article in press as: Ichinose M, et al., Japanese guidelines for adult asthma 2017, Allergology International (2016), http:// dx.doi.org/10.1016/j.alit.2016.12.005 10 M Ichinose et al / Allergology International xxx (2016) 1e27 received an LTRA than in those who have received other anti-asthmatic drugs, it is not yet clear whether an LTRA is directly involved in the onset of EGPA.45 LTRAs are generally safe drugs, but interact with other agents, such as warfarin, since they are also metabolized by CYP2C9 LTRAs seem to be relatively safe for pregnant women e) Sustained-release theophylline: sustained-release theophylline is a long-acting bronchodilator with antiinflammatory effects It exerts bronchodilatory actions via nonselective inhibition of phosphodiesterases It inhibits airway infiltration of lymphocytes and eosinophils,46 a proliferative T cell response, cytokine production, induction of apoptosis in eosinophils,47 and recovery of steroid sensitivity through histone deacetylase (HDAC) reactivation.48 To avoid the adverse effects of theophylline, sustained-release theophylline is used in clinical practice While sustained-release theophylline is clinically less effective than ICSs, when used in combination with lowto-medium doses of an ICS, the same effects as those obtained with an increased ICS dose can be achieved.49 Therefore, sustained-release theophylline is recommended for use when asthma control cannot be achieved by using other bronchodilators However, in patients treated with ICSs, sustained-release theophylline, at a dose of 300e400 mg/day, improved airway obstruction to a lesser extent than LABAs26 and to a comparable (the same or slightly lesser) extent as LTRAs.50 Monitoring of the serum level is useful for avoiding adverse effects Antiinflammatory effects are obtained at a serum theophylline level of 5e10 mg/mL, although bronchodilatory action is achieved in a concentration-dependent manner No serious adverse effects have been noted at serum theophylline concentrations of up to 20 mg/mL Monitoring the peak serum theophylline level is difficult; thus, the target level ranges from to 15 mg/mL The adverse effects of theophylline include gastrointestinal symptoms such as nausea and vomiting at initial oral administration In addition, toxic symptoms may progress to tachycardia and arrhythmia In the most severe cases, convulsions may occur that can lead to death f) Long-acting anti-muscarinic receptor antagonist (LAMA): tiotropium bromide is available as a LAMA controller in Japan It is frequently used in patients with COPD, and a soft mist inhaler (Respimat®) is allowed for use as asthma treatment It should be used in combination with ICSs for long-term management The bronchodilatory effects of tiotropium are sustained for 24 h51,52 and it improves pulmonary function of asthmatic patients with once daily use It improves pulmonary function and reduces exacerbations in severe asthmatic patients who continue to have asthma symptoms even when treated with high doses of ICSs plus LABAs.53 It has been reported that tiotropium improved pulmonary function in asthmatic patients who remained symptomatic after treatment with mild to moderate doses of ICSs.54,55 It also improved pulmonary function in patients carrying the 16Arg/Arg SNP in the ADRB region, to the same extent as Serevent (salmeterol) Dry mouth is sometimes observed as a side-effect of tiotropium Because systemic absorption of tiotropium is much lower, systemic side-effects can be ignored It should not be used in cases with closed-angle glaucoma Dysuria may rarely occur in patients with benign prostatic hypertrophy, but withdrawal of tiotropium improves the dysuria g) Anti-IgE antibody: omalizumab is a humanized antihuman IgE monoclonal antibody In Japan, omalizumab is available for the following asthmatic patients: (i) those who have unstable asthmatic symptoms, even when treated with high doses of ICSs plus more than controller agent; (ii) those who are positive for perennial inhaled antigens, such as house dust; (iii) the dose and frequency of administration are determined based on the dosage conversion table, according to the patient's weight and serum IgE level (30e1500 IU/mL serum IgE) Omalizumab has the following effects in patients with poor asthma control, even despite treatment with a high dose of ICS: (i) it prevents exacerbation; (ii) reduces the frequency of asthmatic symptoms; (iii) improves QOL; (iv) reduces the frequency of emergency room visit and hospital admission; and (v) reduces the steroid dose.56 Omalizumab modestly improves FEV1 and PEF values It has only been confirmed to be effective in poorly controlled patients treated with ICS/LABA Omalizumab should be used as a therapeutic agent in step treatment for severe persistent asthma At 16 weeks after administration, the therapeutic effects can be comprehensively judged and it should then be determined whether the treatment needs to be continued.57 It is effective in about 60% of patients Factors predicting effectiveness are higher serum eosinophil counts and higher levels of FeNO.58 The major adverse effects of omalizumab are pain and swelling at the injection site An anaphylactic reaction, reported as a serious adverse effect in 0.1e0.2% of the non-Japanese patients, could develop within h after administration (about 70% of the episodes), but some reactions have been reported to occur after 24 h There is no evidence that omalizumab causes development of malignancy, but care should be taken with its use, as EGPA may develop due to the reduced amount of systemic steroids No teratogenicity has been reported, but its safety has not been established in pregnant women h) Anti-allergics other than LTRAs: anti-allergic agents include either mediator release suppressants or mediator inhibitors They are categorized as (i) mediator-release suppressants, (ii) histamine H1-antagonists, (iii) thromboxane A2 inhibitors/antagonists, (iv) Th2 cytokine inhibitors A few papers have shown the utility of Th2 cytokine inhibitors with or without ICSs,59,60 but the utility of the other anti-allergics is limited The safety of oral anti-allergic agents in fetuses during pregnancy has not been demonstrated i) Other agents and therapies (i) Bronchial thermoplasty (BT): Bronchial thermoplasty is a novel intervention for severe asthma that delivers controlled thermal energy to the airway wall during a series of bronchoscopy procedures, resulting in a prolonged reduction in ASM mass.61 BT therapy has been approved in Japan since 2015 Only report has stated that BT in patients with severe persistent asthma improves asthma-specific QOL, with a reduction in severe exacerbations and healthcare use in the years post-treatment.61 However, the longterm efficacy and safety of this therapy remain unknown and should be studied in future (ii) Allergen immunotherapy: Allergen immunotherapy is a therapeutic strategy that induces immune tolerance by administration of specific antigens to allergic asthmatics It simultaneously cures allergic rhinitis and allergic keratoconjunctivitis in addition to Please cite this article in press as: Ichinose M, et al., Japanese guidelines for adult asthma 2017, Allergology International (2016), http:// dx.doi.org/10.1016/j.alit.2016.12.005 M Ichinose et al / Allergology International xxx (2016) 1e27 maintain good asthma control using the minimum of drugs Evaluation of control status and adjustment of treatment every 1e3 months are necessary b) Useful considerations for monitoring asthma management i) Spirometry: The measurement of pulmonary function (airflow limitation) is quite important for determining the severity of asthma and evaluating the effectiveness of treatment.78 The degree of airflow limitation is determined by a reduction in FEV1, FEV1% (FEV1% ¼ FEV1/FVC Â 100), and PEF Decreased values of V50 and V25 and increased values of the V50/V25 ratio are useful for early detection of peripheral airway diseases Spirometry should be measured at the first visit and within 1e3 months after treatment, and once a year thereafter ii) PEF: To evaluate the degree of airflow limitation objectively every day in asthmatic patients, monitoring of PEF is recommended It is particularly beneficial in asymptomatic patients or in those with frequent exacerbations It can also be useful for identification of allergens or exacerbation factors Diurnal variation of PEF is correlated with the degree of airway hyperresponsiveness Because large daily variation of PEF indicates increased airway hyperresponsiveness, it is a good marker for evaluating asthma control.79 iii) Asthma diary and questionnaire: An asthma dairy, the Asthma Control Questionnaire (ACQ), and the Asthma Control Test (ACT) are useful for evaluating asthma control.80 iv) Percentage of sputum eosinophils: Sputum induction by inhalation of hypertonic saline is recommended if spontaneous sputum cannot be obtained When sputum is induced, SABA should be inhaled to avoid hypertonic saline-induced bronchoconstriction The management of eosinophil-oriented asthma is reported to be superior to that of symptom-oriented asthma in reducing asthma exacerbations.81 v) Airway hyperresponsiveness: Using the threshold values of airway hyperresponsiveness can achieve better management than that achieved by using conventional symptoms and pulmonary function.82 vi) Measurement of fractional exhaled nitric oxide (FeNO): Exhaled nitric oxide (NO) is derived from the inducible type of NO synthase (iNOS) in airway epithelial cells It reflects the degree of airway eosinophilic inflammation Because measurement of FeNO is easy and non-invasive, it is useful for diagnosis of asthma and monitoring of airway inflammation Moreover, high levels of FeNO are indicative of good responsiveness to steroid treatment.83,84 However, there is little evidence indicating whether monitoring of FeNO can be used for management of asthma in clinical practice vii) Other parameters: Eosinophil counts in the peripheral blood and specific IgE antibodies are sometimes useful for the diagnosis of asthma Blood theophylline concentration or corticosteroid levels are important for monitoring patients receiving asthma pharmacotherapy In asthma exacerbations, respiratory failure should be evaluated by pulse oximeter and arterial blood gas analysis In such cases, blood examination, chest radiography, and electrocardiography should be 13 used for differential diagnosis and diagnosis of complicating diseases (5) Management of difficult-to-treat patients In uncontrolled or partly controlled patients, asthma diagnosis, adequate instructions regarding daily medication, management of complications, and avoidance of exacerbating factors should be monitored If asthmatic patients remain uncontrolled with treatment step 3, they should consult a specialist Management of acute exacerbation needs to be provided with an asthma diary, in which the doses and timing of asthma medication are recorded Patients with worsening symptoms are instructed to follow an emergency manual immediately In addition, patients should be acquainted with dose-reduction strategies Furthermore, in cases of acute exacerbation, they should have contact information handy, addresses of emergency hospitals, and an “asthmatic patient card,” which enables treating physicians and other physicians to administer emergency treatment Early referral to a specialist is recommended for patients with underlying diseases, such as aspirin exacerbated respiratory disease (AERD), eosinophilic granulomatosis with polyangitis (EPGA), other systemic vasculitis, and allergic bronchopulmonary aspergillosis (ABPA), because continuous administration of a systemic steroid or immunosuppressant may be needed in addition to the above treatment step a) AERD (AIA): About 50% of aspirin-induced asthma occurs in refractory asthmatic patients They often have nasal polyps and eosinophilic sinusitis Not only aspirin, but also acidic NSAIDs induce severe asthma attacks; therefore, a physician should instruct patients not to use NSAID-containing oral medicines, suppositories, patches, and ointments A physician should consider treatment of the complicating nasal polyps and eosinophilic sinusitis Management of AERD is similar to that of adult asthma ICSs should be used for longterm management of AERD, and LTRAs have been reported to be effective in AERD In treating acute exacerbations, caution should be exercised for induction of asthma attack by prompt intravenous infusion of some types of steroids When administration of systemic steroids is needed in an asthma attack, oral steroids or intravenous infusion of steroid phosphate esters are recommended b) EPGA: EPGA is also known as CSS, and is characterized by asthma, increase of eosinophil levels in the blood and tissues, and polyangiitis of many organs.85 The treatment of EPGA involves systemic steroids Poor-prognosis factors (a 5-factor score) has been proposed.86 In patients with severe asthma and cardiac disease or in steroid-resistant patients, cyclophosphamide is used in combination with systemic steroids Sometimes, an intravenous infusion of immunoglobulin is administered in treatment-resistant patients with nervous system or cardiac disorders c) ABPM and ABPA: ABPM and ABPA are diseases characterized by asthma and lung infiltration induced by abnormal immunoreactivity against fungi and Aspergillus, resulting in irreversible destruction of the airway architecture (bronchiectasis) and lung fibrosis To avoid progression of lung tissue destruction, early diagnosis is important; however, some cases not fulfill the diagnostic criteria In addition to asthma treatment, systemic steroids are required.87 When the dose of systemic steroids cannot be reduced, administration of antifungal drugs should be considered d) GERD: GERD is a complicating disease in asthmatic patients, and the symptoms of GERD are frequently observed in uncontrolled asthmatic patients Administration of theophylline, Please cite this article in press as: Ichinose M, et al., Japanese guidelines for adult asthma 2017, Allergology International (2016), http:// dx.doi.org/10.1016/j.alit.2016.12.005 14 M Ichinose et al / Allergology International xxx (2016) 1e27 b2-agonists, or oral steroids sometimes exacerbates GERD, which is treated with proton-pump inhibitors Treatment with proton-pump inhibitors does not necessarily improve asthma control in uncontrolled asthmatic patients with asymptomatic GERD e) Asthma with allergic rhinitis: Asthma is significantly complicated by allergic rhinitis Active complicating allergic rhinitis in patients with asthma should be simultaneously treated.88 Pharmacotherapy for allergic rhinitis may alleviate asthma symptoms, inflammation of the lower airways, and improve airway hyperresponsiveness.89 Concomitant use of an LTRA is more effective in improving airway obstruction due to asthma than doubling the dose of an ICS.90 f) Asthma-COPD overlap syndrome (ACOS): COPD is an important coexisting disease in asthma, requiring caution in differential diagnosis in the elderly with asthma COPD is also an important disease as a comorbidity Particularly, elderly patients with asthma, who have a smoking history, should be diagnosed appropriately ACOS is considered as a condition involving both asthma and COPD Because patients with ACOS often have severe symptoms and experience frequent exacerbations, it causes refractoriness of asthma Patients with ACOS should essentially be treated with ICSs, and LAMA or LABA is added to ICS as needed 4.2 Management of acute exacerbations in adults 4.2.1 Therapeutic agents (1) Inhaled short-acting b2-agonists (SABA) Inhaled short-acting b2-agonists (SABA) are the first-line drug for the treatment of acute exacerbations Repeated administration of a small dose (1e2 puffs at a time, using a portable pMDI) exerts better therapeutic effects than a single administration of a high dose.91 For acute exacerbation, a SABA can be inhaled every 20 for the first hour and subsequently every hour until symptom relief is obtained Inhalation with a spacer causes fewer adverse effects and is more efficacious.92 If adverse effects, such as marked tremor or palpitation, develop, the inhalation should be discontinued A nebulizer coupled with oxygen is effective for continued inhalation Adding an inhaled anticholinergic may have an additive bronchodilatory action.93 Patients treated with a combination of budesonide/formoterol (BUD/FM) as both the controller and the reliever medication (SMART), should be instructed to inhale once for exacerbations If the symptoms not improve within a few minutes, more inhalation can be added.94 At maximum, reliever use is limited to inhalations per exacerbation (8 inhalations per day for the total of controller and reliever use) If symptom persists, the patient should visit an outpatient clinic immediately (2) Corticosteroids Corticosteroids (steroids) are recommended for patients experiencing insufficient bronchodilator action, moderate or severe exacerbations, or who are already treated with steroids.95 The initial dose is 200e500 mg of hydrocortisone or 40e125 mg of methylprednisolone,95 followed by subsequent intravenous drip infusion of 100e200 mg of hydrocortisone or 40e80 mg of methylprednisolone every 4e6 h as needed Prednisolone, at a dose of 0.5 mg/kg, can also be administered orally or by intravenous drip infusion Because of the relatively long duration until the clinical effects of the steroids emerge (ca h) and safety, slow intravenous drip infusion for 30e60 is recommended at initial administration When symptoms deteriorate after the initial infusion of steroid succinate esters, including hydrocortisone or methylprednisolone, it should be considered due to steroid-induced exacerbation, and Table 17 High-risk asthma exacerbation group The high-risk group meets any one of the following criteria: Receiving systemic steroid administration, or systemic steroid administration has recently been discontinued History of hospitalization due to asthma attack in the past year Emergency visit due to asthma attack in the past year Tracheal intubation due to asthma attack in the past Coexisting mental disorder Noncompliance with asthma treatment plan Not using an inhaled corticosteroid Excessive use of short-acting b2 agonist another steroid should be substituted In patients with AERD, as steroid succinate esters may induce worsening in 40e60% of patients,96 steroid phosphate esters (i.e., dexamethasone, betamethasone, or another hydrocortisone) should be used Systemic steroid administration is indicated for patients with: (a) moderate-to-severe exacerbations, (b) history of a severe exacerbation requiring systemic steroid, (c) history of a serious exacerbation requiring hospitalization, (d) significant risk factors of exacerbations (Table 17) (3) Oxygen Usually oxygenation should be initiated for patients with SpO2 less than 95% (PaO2 < 80 mmHg) or with symptoms suggesting the existence of hypoxemia (cyanosis, dyspnea, or tachypnea) Maintaining SpO2 at almost 100% is not required and, in turn, can be a risk for delaying the detection of worsening of respiratory failure.97 In case of serious exacerbation, arrangements for endotracheal intubation and ventilator use should be made simultaneously (4) Theophylline The effective serum concentration of theophylline for bronchodilation (8e20 mg/mL in adults) is close to the concentration that causes adverse reactions Intravenous infusion of aminophylline (6 mg/kg) has a bronchodilatory action and is effective in treating acute asthma attacks.98 Aminophylline has additive effects for b2-agonists,98 and its use decreases hospitalization rates due to asthma attacks Aminophylline also has positive effects on respiratory drive and respiratory muscles As there are individual differences in the onset of action and pharmacokinetics, monitoring the level of serum theophylline is recommended Measurement of serum theophylline concentration is covered by medical insurance in Japan as a management charge for therapeutic drug monitoring Caution should be exercised against intoxication in the presence of factors affecting theophylline clearance, as shown in Table 18 For initial administration, mg/kg of aminophylline in 200e250 mL of isotonic fluid is infused for about h If 600 mg or more of sustained-release theophylline per day is already administered, the serum theophylline concentration is above mg/mL, or reduced theophylline clearance is suspected, the aminophylline Table 18 Factors influencing serum theophylline levels Decreased clearance (increases serum level) - Aging, obesity - Hepatopathy, heart failure, viral infection, and fever - Agents: allopurinol, macrolides, cimetidine, diazepam, new quinolones, etc Increased clearance (decreases serum level) - Smoker (!15 cigarettes/day) - Agents: barbiturates, antiepileptics, rifampicin, isoproterenol, etc Please cite this article in press as: Ichinose M, et al., Japanese guidelines for adult asthma 2017, Allergology International (2016), http:// dx.doi.org/10.1016/j.alit.2016.12.005 M Ichinose et al / Allergology International xxx (2016) 1e27 dose should be reduced to half or less If toxic symptoms, including headache, nausea, vomiting, tachycardia, or arrhythmia occur, infusion must be stopped immediately For continuous administration of aminophylline, aminophylline (250 mg) in 500 mL of maintenance infusion fluid is intravenously dripped for 5e7 h (about 0.6e0.8 mg/kg/h) The infusion speed should be adjusted to achieve 8e20 mg/mL of serum theophylline levels If toxic symptoms occur during administration, the drip infusion must be slowed down or discontinued, and the level of theophylline should be measured to rule out overdose (5) Inhaled anticholinergics If the effect of SABA is insufficient, adding anticholinergics can be considered Anticholinergics (ipratropium or oxitropium) added to SABA may enhance the bronchodilator effect, improve symptoms and respiratory function,99 and reduce hospitalization (6) Subcutaneous injection of adrenaline Catecholamine (adrenaline, 0.1%) may be administered when the effects of an inhaled b2-agonist is insufficient Care should be taken for cardiac arrest, arrhythmia, and other adverse effects Subcutaneous injection of adrenaline (0.1%, 0.1e0.3 mL) shows a bronchodilator effect through the bronchial smooth muscles relaxation (b effect) and the improvement in mucosal edema (a effect) Although adrenaline can be administered repeatedly every 20e30 min, pulse rate should be monitored and kept below 130/ Adrenaline is preferably avoided in pregnant women and is contraindicated in patients with arteriosclerosis, diabetes mellitus, glaucoma (except for open-angle glaucoma), hyperthyroidism, psychoneurosis, and severe arrhythmia Hypoxemic patients are at high risk for adverse effects The following agents are contraindicated for concomitant use with adrenaline (i) Inhaled halogencontaining anesthetics, such as halothane, because of an increased risk of tachycardia and ventricular fibrillation (ii) Antipsychotics (butyrophenones, iminodibenzyls, phenothiazines, risperidone, and zotepine) and a-blockers may result in hypotension due to epinephrine reversal (iii) Catecholamine formulation, such as isoproterenol, and adrenergic agents are principally contraindicated, except in emergency cases, such as resuscitation, because concomitant use may develop arrhythmia and cardiac arrest (iv) A tulobuterol patch may be concomitantly used with caution, but fenoterol is contraindicated (7) Antibiotics Administered to patients when bacterial infection is suspected by fever and purulent sputum (8) Fluid replacement Although substantial fluid replacement is generally unnecessary, caution should be exercised for dehydration (9) Analgesics Use of analgesics for severe exacerbation is not recommended because of the possibility of worsening of respiratory conditions 4.2.2 Management at home As the severity of asthma symptoms vary widely, management of exacerbations should be tailored according to their severity, and the approach for managing exacerbations must be relayed to patients individually For this purpose, an action plan with specific instructions for each condition should be provided.100 In case of wheezing/chest tightness and moderate asthma symptoms, 1e2 puffs of a SABA in pMDI should be administered If insufficient, inhalation can be repeated every 20 for h and subsequently 15 once an hour Patients under SMART treatment using BUD/FM can inhale once for exacerbation If the symptoms not improve within a few minutes, more inhalation can be added.94 Patients can be treated at home continuously when symptoms disappear with the use of these agents and their effects persist for 3e4 h However, if sufficient therapeutic effect cannot be obtained, oral prednisolone at 15e30 mg should be administered, and the patient should be referred to an emergency outpatient unit immediately 4.2.3 Treatment procedures in emergency outpatients (Table 19) On arrival at the emergency outpatient clinic, the severity of exacerbation should be immediately determined based on symptoms Exacerbation is classified based on the symptoms as follows: (i) mild: dyspnea without difficulty in lying down; (ii) moderate: difficulty in lying down and walking; (iii) severe: abasia, difficulty in moving and speaking; and (iv) serious symptoms: cyanosis, impaired consciousness, and respiratory arrest Treatment for exacerbations is classified into steps (Table 19) It is also important to take the history quickly and to initiate treatment without delay Important points for history taking are: the extent and duration of exacerbation, recent treatment and steroid use, history of hospitalization and intubation due to asthma, history of AERD or other complications, including drug allergy, cardiac diseases, pneumothorax, and pulmonary embolism (Table 20) After assessment of the severity of exacerbation, the treatment step is selected (Table 21) (1) Wheezing/chest tightness, mild symptoms (mild exacerbations) a) Assessment: Although wheezing and chest tightness is present, normal movements are maintained The term “mild symptoms” indicates mild dyspnea at rest, without difficulty in lying down, but slightly hampered movement Daily activities are not impaired by these symptoms The value of PEF is 80% or more of the predicted value, or the best value after using a bronchodilator For new patients, a history of asthma and already administered treatments should be obtained Radiography and an electrocardiogram is helpful for excluding dyspnea unrelated to asthma b) Treatment: Administer step treatment Inhale SABA in pMDI, DPI, or nebulizer format If symptoms disappear and are stable for 60 without additional treatment, confirm that there is no airway obstruction (%PEF ! 80%) and discharge the patient If symptom improvement is insufficient and airway obstruction persists (%PEF < 80%), proceed to step treatment (2) Moderate symptoms and continuous mild symptoms (moderate exacerbation) a) Assessment: Moderate asthma symptoms include dyspnea and orthopnea at rest, with difficulty in movements The PEF is 60e80% of the predicted or the best value When the patient has already been diagnosed with asthma, examination for exacerbation can be performed as usual For new patients, a differential diagnosis of other diseases by arterial blood gas analysis, blood count, chest radiography, and electrocardiogram should be considered When SpO2 is less than 92%, arterial blood gas analysis should be performed to rule out hypercapnia b) Treatment: Administer step treatment for asthma exacerbations Please cite this article in press as: Ichinose M, et al., Japanese guidelines for adult asthma 2017, Allergology International (2016), http:// dx.doi.org/10.1016/j.alit.2016.12.005 16 M Ichinose et al / Allergology International xxx (2016) 1e27 Table 19 Treatment steps for asthma exacerbation Treatment Home remedy, emergency visit and hospitalization, and ICU treatmenty Treatment step Inhaled short-acting b2-agonist (SABA) Additional inhalation of budesonide/formoterol, as neededz Home remedy Treatment step Repeated inhalation of SABA using a nebulizerx Intravenous drip infusion of aminophylline¶ Oxygen (target SpO2 at 95%) Systemic administration of steroidk Inhaled anticholinergics Subcutaneous injection of Bosmin® (adrenaline, 0.1%)# Emergency visit - If symptoms improve within h, the patient may be discharged - Insufficient response within 2e4 h - No response within 1e2 h Hospital admission: Switch to treatment step as for severe exacerbation Treatment step Repeated inhalation of SABA using a nebulizerx Repeated administration of systemic steroidk Oxygen (target SpO2 at 95%) Intravenous drip infusion of aminophylline (continuous)yy Inhaled anticholinergics Subcutaneous injection of Bosmin® (adrenaline, 0.1%)# Emergency visit If no response within h, hospitalization If exacerbated, switch to treatment for serious exacerbation Treatment step Immediate hospitalization and ICU treatmenty Continue the above treatment If symptoms and respiratory function are exacerbated, conduct intubation.y Despite oxygen inhalation, 50 mmHg PaO2 and/or rapidly elevated PaCO2 with impaired consciousness Mechanical ventilation,y Bronchial lavage Consider general anesthesia (using isoflurane, sevoflurane, etc.) Aim of treatment: Elimination of dyspnea, normal movement, normal sleep, and normal everyday life PEF rate is !80% of the predicted value or the best value Oxygen saturation >95% (values after bronchodilator administration) No exacerbation of asthma symptoms by routine medication and inhalation Consider treatment step-up when the aim of treatment cannot be achieved within h y ICU or hospital rooms where tracheal intubation, assisted ventilation, bronchial lavage, etc., can be performed and continuous monitoring can be conducted using a sphygmomanometer, electrocardiogram, and pulse oximeter Since intubation and mechanical ventilation during severe respiratory insufficiency are often life-threatening, they should be used by experienced specialists when inevitable in emergency z Repeat 1e2 puffs of SABA pMDI twice at an interval of 20 x Inhalation of SABA using a nebulizer: repeat every 20e30 Monitor the pulse, which should be maintained at 130/min ¶ Intravenous drip infusion of aminophylline (6 mg/kg) in 200e250 mL of isotonic fluid: Administer for about h If adverse reactions occur, discontinue the infusion When a sufficient amount of theophylline had been administered before exacerbation, reduce the dose of aminophylline to half or less Routinely, measure serum theophylline levels in patients receiving this drug, wherever possible k Intravenous drip infusion of steroids: intravenous drip infusion of 200e500 mg of hydrocortisone, 40e125 mg of methylprednisolone, or 4e8 mg of dexamethasone or betamethasone Subsequently, conduct intravenous drip infusion of 100e200 mg of hydrocortisone, or 40e80 mg of methylprednisolone every 4e6 h as needed, or 4e8 mg of dexamethasone or betamethasone every h as needed, or oral prednisolone (0.5 mg/kg/day) Steroid succinate esters (i.e., methyl prednisolone, prednisolone sodium succinate) should be avoided in patients who have or are suspected of having aspirin-induced asthma # Bosmin® (adrenaline, 0.1%): Bosmin® (0.1e0.3 mL) can be repeatedly administered at intervals of 20e30 Monitor the pulse to be maintained at 30/min This agent is contraindicated in patients with ischemic heart disease, glaucoma (except for open-angle [simple] glaucoma), and hyperthyroidism Sphygmomanometry and electrocardiography are required for patients with hypertension yy Continuous intravenous infusion of aminophylline: following the first intravenous infusion (see ¶ above), conduct continuous intravenous infusion of 250 mg of aminophylline for 5e7 h (about 0.6e0.8 mg/kg/h) Monitor serum theophylline levels which shoud be maintained at 10e20 mg/mL (15e20 mg/mL to achieve the maximum effects) If adverse reactions occur, discontinue the infusion (i) Administer 0.3e0.5 mL of SABA diluted in physiological saline, via a nebulizer, and repeat every 20e30 until symptoms improve A SABA in a pMDI with a spacer has the same efficacy The pulse rate should be maintained below 130/min If symptoms improve within 60 and are stable for 60 after the last administration (%PEF ! 80%) and SpO2 is 95% or higher, the patient can be discharged If improvement is insufficient (%PEF < 80%), the following treatments should be initiated Table 20 Important points for history-taking in an emergency outpatient unit - Time of onset and cause of exacerbations - Extent of exercise limitation and sleep disturbance - History of recent drug administration, names of drugs and time of their last administration, and use of steroids - Hospitalization and emergency visit due to asthma - History of respiratory failure and intubation due to asthma - Cardiopulmonary diseases and complications (heart failure, pneumothorax, pulmonary embolism) - History of AERD and drug allergies (ii) Intravenous drip infusion of 200e500 mg of hydrocortisone, 40e125 mg of methylprednisolone, or 4e8 mg of dexamethasone or betamethasone: systemic steroid should be administered immediately in cases of moderate or more severe exacerbations, poor response to the initial SABA inhalation, current treatment with a high dose ICS (equivalent to FP ! 800 mg/ day) or an oral corticosteroid on regular basis, or highrisk group (Table 18).101 Patients with or suspected of AERD should be treated using steroid phosphate esters Slow intravenous infusion for about an hour is recommended for patients with unconfirmed AERD, or patients who are receiving the agent for the first time (iii) Oxygen: Oxygenation should be initiated nasally at a dose of 1e2 L/min to patients with SpO2 less than 95% (PaO2 < 80 mmHg), or with symptoms suggesting hypoxemia (cyanosis, dyspnea, or tachypnea) (iv) Intravenous infusion of mg/kg of aminophylline in 200e250 mL of isotonic fluid: administer for about h If sufficient theophylline had already been administered, reduce the aminophylline dose to half of this dose or less If adverse reactions to theophylline (arrhythmia, AERD, aspirin-exacerbated respiratory disease Please cite this article in press as: Ichinose M, et al., Japanese guidelines for adult asthma 2017, Allergology International (2016), http:// dx.doi.org/10.1016/j.alit.2016.12.005 M Ichinose et al / Allergology International xxx (2016) 1e27 17 Table 21 Severity of an asthma attack and the corresponding treatment step Exacerbation intensity Dyspnea Movement Measured valuesy Treatment steps in exacerbation PEF SpO2 PaO2 PaCO2 !80% !96% Normal 60 mmHg